Inhibition of protein arginine methyltransferase 5 enhances hepatic mitochondrial biogenesis

Abstract

Protein arginine methyltransferase 5 (PRMT5) regulates gene expression either transcriptionally by symmetric dimethylation of arginine residues on histones H4R3, H3R8, and H2AR3 or at the posttranslational level by methylation of nonhistone target proteins. Although emerging evidence suggests that PRMT5 functions as an oncogene, its role in metabolic diseases is not well-defined. We investigated the role of PRMT5 in promoting high-fat-induced hepatic steatosis. A high-fat diet up-regulated PRMT5 levels in the liver but not in other metabolically relevant tissues such as skeletal muscle or white and brown adipose tissue. This was associated with repression of master transcription regulators involved in mitochondrial biogenesis. In contrast, lentiviral short hairpin RNA-mediated reduction of PRMT5 significantly decreased phosphatidylinositol 3-kinase/AKT signaling in mouse AML12 liver cells. PRMT5 knockdown or knockout decreased basal AKT phosphorylation but boosted the expression of peroxisome proliferator-activated receptor α (PPARα) and PGC-1α with a concomitant increase in mitochondrial biogenesis. Moreover, by overexpressing an exogenous WT or enzyme-dead mutant PRMT5 or by inhibiting PRMT5 enzymatic activity with a small-molecule inhibitor, we demonstrated that the enzymatic activity of PRMT5 is required for regulation of PPARα and PGC-1α expression and mitochondrial biogenesis. Our results suggest that targeting PRMT5 may have therapeutic potential for the treatment of fatty liver.

Selective PRMT5 Inhibitors Suppress Human CD8+ T Cells by Upregulation of p53 and Impairment of the AKT Pathway Similar to the Tumor Metabolite MTA

“…Of note, EPZ015666 impaired the activation of the AKT/mTOR signaling cascade in a similar manner as it has already been shown for MTA (21). This is in accordance with previous studies reporting a correlation between PRMT5 expression and AKT phosphorylation in different cell lines (44,45). For the first time, our metabolic studies further expand these observations demonstrating an inhibitory impact of MTA and synthetic PRMT5 inhibition on T-cell metabolism.…”

Protein arginine methyltransferase 5 promotes metastasis via enhancing EGFR transcription and modulating AKT1 activation by methylation

“…ActivSignal IPAD assay. The signal transduction pathway analysis was performed as previously reported 39 . Briefly, the whole-cell lysate was submitted to ActivSignal for analyzing the expression or phosphorylation of 70 pivotal proteins involved in more than 20 signaling pathways.…”

“…Arginine methylation plays a critical role in transcriptional regulation through histone arginine methylation, but also via modification of glycine-arginine rich motifs RGG/RG) involved in protein/DNA and protein/protein interactions 35,36 . We have previously shown that PRMT5 increases the expression of the adipogenic master transcriptional factor PPARγ2 during pre-adipocyte differentiation 37,38 , and elevates AKT2 activation in hepatocytes in response to dietary fatty acid stimulation 39 . Our initial findings suggested the clinical relevance of PRMT5 in neuroblastoma.…”

“…Human pCDNA3-Flag-HA-AKT1, pCDNA6A-EGFR, and pHIV-iRFP720-E2A-Luc were purchased from Addgene. pCDNA3.1-Flag-PRMT5 wild type and dead enzyme mutant were as described previously39 . pCDNA3-Flag-HA-AKT1 15G/K mutant was generated by sitemutagenesis using QuickChange Lightning Site-Directed Mutagenesis Kit following the manufacturer's protocol (Agilent).…”

miR-21 regulates growth and EMT in lung cancer cells via PTEN Akt GSK3 beta signaling

“…Immunofluorescence was performed according to the standard procedures as described previously (11). A549 and ASTC-a-1 cells were cultured on glass cover slips and incubated overnight to establish adherence.…”